Nosocomial infection is an important problem to be solved by modern medicine because it threatens patient lives and also, for hospitals, it extends the periods of hospitalization and causes excessive medical expenses. Main routs of nosocomial infection include (1) medicine contamination during preparation of medicines, and (2) contamination of routes of medicine administration. As a preventive measure against the contamination, (1) a preparation pre-filled in a syringe is used for decreasing the opportunity of medicine contamination, and (2) a medical apparatus with a closed flow path is developed for decreasing the contamination of routes of administration.
An intravascular indwelling catheter is a tube inserted into a blood vessel in order to administer an infusion preparation or medicine into blood. In medical practice, a peripheral venous catheter and a central venous catheter are frequently used for access to blood vessels, and these catheters are typical examples of the intravascular indwelling catheter. The intravascular indwelling catheter is considered as a source of nosocomial infection and seen as a problem. For example, an intravascular catheter induces local infection, bloodstream infection, or septicemia. As countermeasures against this, various approaches such as the establishment of guidelines (Non-patent Document 1 below) have been made. As one of the approaches, in the case of a patient who is treated with an infusion through the intravascular indwelling catheter over a long period of time, catheter lock is performed for preventing occlusion of the catheter in a routine operation in which for the reason of bathing or bedding, an infusion line is removed from the patient, leaving the intravascular indwelling catheter indwelled.
The catheter lock includes filling a catheter with physiological saline or heparin diluted with physiological saline as a catheter lock solution, and enclosing the solution generally for about 24 hours. As the catheter lock solution, heparin-saline having an anticoagulant action is often used, but in some cases, a physiological saline is used for locking a peripheral venous catheter for a short time. Intravascular indwelling of a catheter locked with the catheter lock solution is widely conduced because it is advantageous in that the frequency of needling to a patient is decreased, and the time required for a medical staff to insert a catheter is reduced. However, when a catheter is contaminated with bacteria during catheter lock, the bacteria proliferate in the catheter warmed by the body temperature, and sometimes a biofilm is formed to cause the risk of infection. For example, in 2002 in Japan, a heparin-saline solution prepared in advance was contaminated with bacteria, and patients administered with the heparin-saline solution as a catheter lock solution developed septicemia one after another, leading to death of several patients. With this accident as a turning point, the risk of infection with catheter lock solutions is recognized (Non-patent Document 2 below), and in principle, catheter lock solutions composed of heparin are prohibited from being prepared in advance in hospitals.
Disclosed is a syringe filled with a solution which is characterized by containing 1 to 100 units/mL of heparin, being physiologically isotonic, and having a pH 6 or more, without containing a preservative (Patent Document 1). This catheter lock solution is an aseptic preparation pre-filled in a syringe and is sold, and thus the opportunity of contamination during preparation in a hospital is decreased, thereby possibly decreasing nosocomial infection. However, the catheter lock solution, i.e., physiological saline or heparin-saline, does not have an antimicrobial/bacteriostatic action and thus bacteria proliferate when contaminated with bacteria as shown by data later, and thus it cannot be easily said that nosocomial infection is eradicated. That is, even when a patient is administered with an aseptic catheter solution pre-filled in a separate container connected to an administration line such as an infusion set, there is the risk of contamination of the catheter with bacteria due to the use of the contaminated infusion set or improper treatment and operation by a practitioner. As a result, bacteria proliferate in the catheter lock solution, and a large amount of bacteria enter the blood stream, thereby causing serous infections. In particular, in the case of an intravascular indwelling catheter, the catheter lock solution comes in contact with blood in the catheter and thus creates an environment more suitable for bacterial proliferation due to blood-derived nutrient sources.
A heparin preparation with the antimicrobial action, which contains, as a preservative, methyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol, cresol, phenol, or benzyl alcohol, is sold. However, it is reported that administration of a large amount of benzyl alcohol brings about dyspnea or allergy reaction (Non-Patent Document 3 below), and the above-described toxic preservative agent is no longer used from the viewpoint of safety. In addition, in order to prevent catheter-related bloodstream infection, an antibiotic lock method has been attempted, in which a lumen of a catheter is flushed and filled with a solution of vancomycin which is an antibiotic, and the effect has been proved (Non-Patent Documents 4, 5, and 6). However, according to the guidelines of Non-Patent Document 1, this method is not recommended from the viewpoint of the risk of producing resistant bacteria.
Also, an anticoagulant agent/antimicrobial agent combination containing minocycline as an antibiotic and ethylenediaminetetraacetic acid has been proposed as a catheter lock solution and investigated (Non-Patent Document 7 below). Further, a concentrated citrate solution is disclosed as a catheter lock solution for decreasing infections (Patent Document 2 below), but bacteremia is improved by the antimicrobial action of a 47% hypertonic citrate solution (supposed to be about 6000 mOs) as shown in Examples. Such a high-concentration citrate lock solution remote from physiological osmotic pressure have the concern about safety because it takes in blood calcium and forms a complex, thereby possibly causing the occurrence of hypocalcemia or the like.    Patent Document 1: Japanese Unexamined Patent Application Publication No. 2003-183154    Patent Document 2: Japanese Unexamined Patent Application Publication (Translation of PCT Application) No. 2002-523336    Non-Patent Document 1: Guidelines for the Prevention of Intravascular Catheter-Related infections (CDC) (Untied States, Morbidity and Mortality Weekly Report, Aug. 9, 2002)    Non-Patent Document 2: “Thoroughgoing Preventive Measure against Nosocomial Infection with Serratia”, Ministry of Health, Labor and Welfare, Pharmaceutical and Food Safety Bureau, Safety Division Information (Pharmaceutical and Medical Safety No. 0719001, Jul. 19, 2002)    Non-Patent Document 3: Drug Intell Clin Pharm, 9, p 154, 1975    Non-Patent Document 4: Henrickson K J, Axtell R A, Hoover S M, et al.Prevention of central venous catheter-related infections and thrombotic events in immunocompromised children by the use of vancomycin/ciprofloxacin/heparin flush solution: A randomized, multicenter, double-blind trial (J Clin Oncol 2000; 18: 1269-78)    Non-Patent Document 5: Carratala J, Niubo J, Fernandez-Sevilla A, et al.Randomized, doubleblind trial of an antibiotic-lock technique for prevention of grampositive central venous catheter-related infection in neutropenic patients with cancer (Antimicrob Agents Chemother 1999; 43: 2200-4)
Non-Patent Document 6: Schwartz C, Henrickson K J, Roghmann K, Powell K,
PREVENTION OF BACTEREMIA ATTRIBUTED TO LUMINAL COLONIZATION OF TUNNELED CENTRAL VENOUS CATHETERS WITH VANCOMYCIN-SUSCEPTIBLE ORGANISMS (J CLIN ONCOL 1990; 8: 1591-7)
Non-Patent Document 7: Raad I I, Buzaid A, Rhyne J, et al.
Minocycline and ethylenediaminetetraacetate for the prevention of recurrent vascular catheter infections (Clin Infect Dis 1997; 25: 149-51)